Project title: The effects of context and physiological state on mesolimbic encoding of reward PROJECT SUMMARY/ABSTRACT The encoding of reward is a complex process that is regulated by a variety of factors that extend beyond primary stimulus features to include interactions between contextual and discrete cues in the environment and changes to physiological state. In general, the encoding of reward and subsequent goal-oriented behaviors are often adaptive and essential for survival. However, humans world-wide are often bombarded with environmental contextual cues that can trigger maladaptive reward-seeking behaviors that are rampant in prominent health issues like obesity and drug addiction. While many have studied the mesolimbic system under the lens of both adaptive and maladaptive goal-directed behaviors, surprisingly little is known about the contribution of contextual cues in modulating the mesolimbic system. Moreover, the functions of the mesolimbic system are powerfully modulated by physiological state and can influence how mesolimbic phasic dopamine responses encode particular outcomes (e.g. food, water, and drugs of abuse). [[Thus, a major aim of this proposal is to delineate the neural substrates that integrate information about contextual cues, discrete cues, and physiological state, which subsequently guide goal- oriented behaviors. VTA-NAc phasic dopamine activity has been strongly implicated in goal-directed behaviors and is robustly influenced by physiological state. In Aim I, we utilize in vivo fiber photometry in awake, behaving animals to generate real-time recordings from VTA dopamine neurons while animals learn to associate water availability with discrete cues. We then examine the thirst neurons of the subfornical organ (SFO) as a primary neural substrate that relays physiological state information to VTA dopamine neurons using fiber photometry and chemogenetic manipulations. Based on previous work and pilot data, we anticipate that the SFO is necessary and sufficient for the modulation of water-cue evoked VTA phasic dopamine activity. We will also determine the multi-synaptic path by which the SFO communicates with the VTA. In Aim II, we consider VTA phasic dopamine signaling as an integrator of both physiological state and contextual cues that is in part modulated by input from the ventral hippocampus (vHP). Here we use fiber photometry in VTA dopamine neurons in conjunction with vHP chemogenetics during a novel behavioral task where animals learn to associate water availability with contexts paired with either water-deprivation or water- satiation. When water-satiated, we expect water-deprivation contexts to augment water-cue evoked VTA phasic dopamine signaling and that this response is dependent on vHP mediated context processing. Taken together, the novel findings from these studies will allow for a greater understanding of how goal-directed behaviors are acquired and expressed within the brain and provide important mechanistic data that will strongly impact the treatment of health issues such as obesity and drug addiction.]]